Nectin-4 is a protein found on the surface of human cells and is a member of the nectin family of molecules. These proteins are involved in various important cellular processes within the body. Nectin-4 contains specific structural features that contribute to its function and interactions with other molecules.
The Biological Role of Nectin-4
Nectin-4 serves as a cell adhesion molecule, holding cells together to form tissues. It facilitates stable connections between adjacent cells, which is crucial for maintaining the structural integrity of various body tissues.
Nectin-4 participates in cell-cell junction formation by binding to other adhesion molecules on neighboring cells. These interactions are calcium-independent, meaning they do not require calcium ions to form stable bonds.
While widely expressed during embryonic development, nectin-4 is found at low levels in healthy adult tissues. It is particularly present in epithelial tissues, such as the skin and the urothelium, which lines the bladder and urinary tract.
Nectin-4’s Connection to Cancer
In cancer, cells can produce certain proteins in much higher amounts than normal, a process known as overexpression. Nectin-4 is significantly overexpressed on the surface of various cancer cells, contrasting with its limited expression in healthy adult tissues. This increased presence is a hallmark in many malignancies.
Nectin-4’s heightened expression is notably associated with urothelial carcinoma, a type of bladder cancer. Studies show that a high percentage of bladder tumors, approximately 60% or more, exhibit moderate to strong nectin-4 staining.
Beyond bladder cancer, elevated nectin-4 expression has also been observed in other cancer types, including breast cancer, pancreatic cancer, and lung cancer. For instance, around 53% of breast tumor specimens show moderate to strong nectin-4 expression. This broader presence across different solid tumors highlights nectin-4 as a protein of interest in the development of new cancer treatments.
Targeting Nectin-4 for Cancer Treatment
Leveraging the overexpression of nectin-4 on cancer cells, Antibody-Drug Conjugates (ADCs) have emerged as a therapeutic strategy. An ADC is designed to deliver a potent anticancer drug directly to tumor cells while minimizing harm to healthy tissues.
The ADC is composed of three main parts: an antibody, a linker, and a chemotherapy drug payload. The antibody specifically binds to nectin-4 proteins on the surface of cancer cells. Once bound, the ADC is internalized by the cancer cell, bringing the attached chemotherapy drug inside.
The chemotherapy drug, or payload, is a potent agent that disrupts cell division and leads to cell death. For nectin-4 targeting, the common payload used is monomethyl auristatin E (MMAE), which works by interfering with cell growth. Once inside the cancer cell, the linker breaks, releasing the MMAE.
Enfortumab vedotin (brand name: Padcev) is an FDA-approved ADC that targets nectin-4. It consists of a human anti-nectin-4 antibody linked to MMAE. This drug effectively binds to nectin-4-expressing cells and induces cell death in various cancers, including bladder, breast, pancreatic, and lung cancers.
Clinical Significance and Patient Implications
The development of nectin-4 targeting therapies, particularly enfortumab vedotin, has significantly impacted the treatment landscape for patients with advanced or metastatic urothelial cancer. This treatment offers a valuable option for individuals whose cancer has progressed after initial therapies, such as platinum-based chemotherapy or immune checkpoint inhibitors. For some patients, this approach has resulted in notable improvements in outcomes, including extended survival.
Before initiating treatment, doctors may test tumor samples for nectin-4 expression. This helps determine if a patient’s tumor expresses sufficient levels of the protein, indicating they may be a suitable candidate. Higher nectin-4 expression levels in tumors have been associated with better responses to enfortumab vedotin.
Despite its targeted nature, treatment with enfortumab vedotin can cause side effects. Common adverse events include skin reactions, fatigue, hair loss, and peripheral neuropathy. Skin reactions can occur because nectin-4 is also expressed at low levels in normal skin cells. Other side effects, like peripheral neuropathy, are primarily linked to the chemotherapy payload, MMAE.